Abstract: Stretch Sensitive Neurons & Lower Esophageal Sphincter Relaxation The lower esophageal sphincter guards the entrance from the esophagus to the stomach, its incompetence (too much relaxation) leads to gastro-esophageal reflux (GER) and heartburn which is one of the most prevalent medical conditions. The impaired LES relaxation (or little relaxation) is the hallmark of achalasia of the esophagus and possibly other spastic motor disorders of the esophagus. Therefore, it is quite apparent that LES dysfunction contributes to significant medical morbidity and health related costs. Our current understanding is that the LES relaxation is neurogenic; it result from activation of the inhibitory neurons located in the myenteric plexus. How does the inhibitory myenteric neuron gets activated is not entirely clear. Current thinking is that preganglionic fibers of the vagus nerve synapse with the inhibitory motor neuron of the LES. The inhibitory motor neuron is located in the myenteric plexus of the lower esophageal sphincter. Contrary to current paradigm, our preliminary studies suggest a role of axial stretch in the activation of the inhibitory myenteric neuron to the LES. Under physiologic conditions, the axial stretch of the LES is caused by esophageal longitudinal muscle contraction. Based on a large number of studies, it is felt that the interstitial cells of Cajal (ICC) mediate neural transmission between the myenteric neurons and smooth muscle cells. Furthermore, ICC's are thought to act as mechanosensors in the gastrointestinal tract. We plan to determine the role of ICC in stretch mediated responses in the LES. We hope that an improved understanding of the mechanism of LES relaxation will results in better strategies to treat reflux disease and spastic motor disorders of the esophagus. The specific goals of our studies are to determine: 1; the mechanism of stretch-activated responses in the mice lower esophageal sphincter - role of stretch sensitive neuron and ICC in the LES relaxation 2; the role of stretch sensitive neurons in the physiologic LES relaxation, i.e., swallow, balloon-distension and electrical stimulation of the vagus nerve induced LES relaxation 3; the effect of Nissen fundoplication on the axial stretch activated LES relaxation PUBLIC HEALTH RELEVANCE: Project Narrative: Significance and Relevance to Veterans Health: A large number of our veterans suffer from disorders of the esophagus; i.e., reflux disease and spastic motor disorders. Heartburn, regurgitation, chest pain and difficulty swallowing are some of the symptoms related to these disorders. The prevalence of reflux disease and associated complications resulting from reflux disease such as Barrett's esophagus and esophageal cancer is generally felt to be greater in the veterans as compared to general population. Lower esophageal sphincter or a valve like mechanism between the esophagus and stomach plays an important role in reflux disease and spastic motor disorders of the esophagus. Based on our observations, motor disorders of the esophagus are related to poor relaxation of the lower esophageal sphincter and the fundamental abnormality in reflux disease is too much relaxation of the lower esophageal sphincter. Therefore, a better understanding of the mechanisms of sphincter relaxation is likely to lead to better treatment strategies in all forms of esophageal motor dysfunctions. The goal of our studies is to enhance our understanding of the mechanism of lower esophageal sphincter relaxation.